Heteroaryl halides, cross-coupling with alkynes

The reaction of heterocyclic lithium derivatives with organic halides to form a C-C bond has been discussed in Section 3.3.3.8.2. This cannot, however, be extended to aryl, alkenyl or heteroaryl halides in which the halogen is attached to an sp2 carbon. Such cross-coupling can be successfully achieved by nickel or palladium-catalyzed reaction of the unsaturated organohalide with a suitable heterocyclic metal derivative. The metal is usually zinc, magnesium, boron or tin occasionally lithium, mercury, copper, and silicon derivatives of thiophene have also found application in such reactions. In addition to this type, the Pd-catalyzed reaction of halogenated heterocycles with suitable alkenes and alkynes, usually referred to as the Heck reaction, is also discussed in this section. 

Since its discovery, the Songashira reaction has been a valuable tool for the functionalization of aromatic and heteroaromatic halides with the versatile alkyne function [9]. Among the many possible alkyne transformations, these derivatives can undergo cyclization reactions to prepare indoles, benzo- and heteroaryl- furans, and other useful pharmacophores. One of the difficulties of the reaction is the propensity of acetylenes to oxidatively dimerize under the reaction conditions, particularly when the cross-coupling reaction is slow as in the case of aromatic... 

A solvent-free variant used octahedral CU2O nanoparticles with added PPhj ligand, which effectively catalyzed the cross-coupling reactions of various aryl and heteroaryl halides with terminal alkynes [148]. The catalyst was reusable without any observable loss of activity, but worked only at temperatures above 100 °C. Further improvements to this approach involved the elimination of the Hgand and carrying out the reaction in a mixture of DMSO, K2CO3, and catalytic amounts of CU2O nanoparticles [149]. 

Abstract The selective catalytic activation/functionalization of sp C-H bonds is expected to improve synthesis methods by better step number and atom economy. This chapter describes the recent achievements of ruthenium(II) catalysed transformations of sp C-H bonds for cross-coupled C-C bond formation. First arylation and heteroarylation with aromatic halides of a variety of (hetero)arenes, that are directed at ortho position by heterocycle or imine groups, are presented. The role of carboxylate partners is shown for Ru(II) catalysts that are able to operate profitably in water and to selectively produce diarylated or monoarylated products. The alkylation of (hetero)arenes with primary and secondary alkylhalides, and by hydroarylation of alkene C=C bonds is presented. The recent access to functional alkenes via oxidative dehydrogenative functionalization of C-H bonds with alkenes first, and then with alkynes, is shown to be catalysed by a Ru(ll) species associated with a silver salt in the presence of an oxidant such as Cu(OAc)2. Finally the catalytic oxidative annulations with alkynes to rapidly form a variety of heterocycles are described by initial activation of C-H followed by that of N-H or O-H bonds and by formation of a second C-C bond on reaction with C=0, C=N, and sp C-H bonds. Most catalytic cycles leading from C-H to C-C bond are discussed. 

Cross-coupling reactions of alkynes. Terminal alkynes undergo high yield Pd(0) catalyzed coupling reaction (72-76) with organic electrophiles. The electrophiles include vinyl, aryl, and heteroaryl halides (72-75) vinyl triflates (77J8) aryl (56,78) and heteroaryl triflates (75,78) and polyfluorophenyl perfluoroalkane sulfonates (79). Several examples are shown in equation 23 - 27 (respectively references 78,72,73,78,79). 

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